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Spinocerebellar ataxia Type 3 (SCA3), the most common dominantly inherited ataxia, is a polyglutamine neurodegenerative disease for which there is no disease-modifying therapy. The polyglutamine-encoding CAG repeat expansion in theATXN3gene results in expression of a mutant form of the ATXN3 protein, a deubiquitinase that causes selective neurodegeneration despite being widely expressed. The mechanisms driving neurodegeneration in SCA3 are unclear. Research to date, however, has focused almost exclusively on neurons. Here, using equal male and female age-matched transgenic mice expressing full-length human mutantATXN3, we identified early and robust transcriptional changes in selectively vulnerable brain regions that implicate oligodendrocytes in disease pathogenesis. We mapped transcriptional changes across early, mid, and late stages of disease in two selectively vulnerable brain regions: the cerebellum and brainstem. The most significant disease-associated module through weighted gene coexpression network analysis revealed dysfunction in SCA3 oligodendrocyte maturation. These results reflect a toxic gain-of-function mechanism, asATXN3KO mice do not exhibit any impairments in oligodendrocyte maturation. Genetic crosses to reporter mice revealed a marked reduction in mature oligodendrocytes in SCA3-disease vulnerable brain regions, and ultrastructural microscopy confirmed abnormalities in axonal myelination. Further study of isolated oligodendrocyte precursor cells from SCA3 mice established that this impairment in oligodendrocyte maturation is a cell-autonomous process. We conclude that SCA3 is not simply a disease of neurons, and the search for therapeutic strategies and disease biomarkers will need to account for non-neuronal involvement in SCA3 pathogenesis.SIGNIFICANCE STATEMENTDespite advances in spinocerebellar ataxia Type 3 (SCA3) disease understanding, much remains unknown about how the disease gene causes brain dysfunction ultimately leading to cell death. We completed a longitudinal transcriptomic analysis of vulnerable brain regions in SCA3 mice to define the earliest and most robust changes across disease progression. Through gene network analyses followed up with biochemical and histologic studies in SCA3 mice, we provide evidence for severe dysfunction in oligodendrocyte maturation early in SCA3 pathogenesis. Our results advance understanding of SCA3 disease mechanisms, identify additional routes for therapeutic intervention, and may provide broader insight into polyglutamine diseases beyond SCA3.

Die Nachfrage fur bildgesteuerte Nierenbiopsien hat durch die erhohte Detektion von Nierenlasionen zugenommen. Trotz der modernen Bildgebung konnen viele kleine Nierentumoren jedoch nicht als gutartig eingestuft werden, da sie von Nierenzellkarzinomen nicht unterscheidbar sind. Die Ultraschall- oder CT-gezielte Nierenbiopsie kann als sichere und genaue Methode in der Diagnostik von Nierenlasionen hilfreich bei der Wahl neuer ablativer und medikamentoser Therapieformen sein und unnotige Operationen vermeiden. Dieser Artikel beschreibt die klinischen Situationen, in denen eine bioptische Sicherung sinnvoll ist, und beleuchtet die Faktoren, die bei der Durchfuhrung einer Biopsie beachtet werden sollten.

Marine ecosystems are subject to anthropogenic change at global, regional and local scales. Global drivers interact with regional- and local-scale impacts of both a chronic and acute nature. Natural fluctuations and those driven by climate change need to be understood to diagnose local- and regional-scale impacts, and to inform assessments of recovery. Three case studies are used to illustrate the need for long-term studies: (i) separation of the influence of fishing pressure from climate change on bottom fish in the English Channel; (ii) recovery of rocky shore assemblages from the Torrey Canyon oil spill in the southwest of England; (iii) interaction of climate change and chronic Tributyltin pollution affecting recovery of rocky shore populations following the Torrey Canyon oil spill. We emphasize that "baselines" or "reference states" are better viewed as envelopes that are dependent on the time window of observation. Recommendations are made for adaptive management in a rapidly changing world.

Aryl electrophiles containing tethered allylboronate units undergo efficient intramolecular coupling in the presence of a chiral palladium catalyst to give enantioenriched carbocyclic products. The reaction is found to be quite general, affording 5, 6, and 7-membered carbocyclic products as single regioisomers and with moderate enantioselectivities. Examination of differential coupling partners points to rapid allyl-equilibration as a key stereodefining feature.

Results from 3,263 QuantiFERON-TB Gold in-tube (QFT-GIT) assays were analyzed to determine the impact of age on test performance. The proportion of indeterminate results was significantly higher in pediatric and elderly (9.1% and 7.4%, respectively) than in adult (2.6%; chi-square test, P < 0.0001) patients. A detailed analysis of indeterminate QFT-GIT assay results is presented.

The detection of a novel coronavirus in patients from the Arabian Peninsula in late 2012 raised serious concerns of a possible international outbreak. Ministries of health of the three affected countries invited missions from the World Health Organization to participate in a review of data and capacity to detect and respond to further cases. Recommendations were made for investigations to answer critical questions about human-to-human transmission and the geographic extent of the virus. Additional recommendations were made to improve surveillance capacity by acquiring the capacity to test for the virus and enhance syndromic surveillance. Available evidence continues to suggest an unknown animal reservoir for the virus with sporadic zoonotic transmission the primary epidemiological pattern of transmission. Human-to-human transmission, while it can occur, does not appear to be sustained in the community.

We control a two mass system with uncertain parameter values, encompassing friction and hysteretic effects, modelled as a functional differential equation. As opposed to control strategies invoking identification mechanisms or neural networks, we propose controllers relying on structural system properties only. Output behaviour with pre-specified accuracy is guaranteed by the funnel controller, active damping of the shaft oscillation by the high-pass filter, zero tracking output error in the steady state by the PI-controller and bounded input disturbances are rejected. Finally, the controllers are implemented on a real plant, an electrical drive.

Forty-three patients with clinically and biochemically unequivocally defined type III hyperlipoproteinemia (HLP) were screened for the presence of the apolipoprotein (apo) B-100 arginine3500-->glutamine mutation. This receptor-binding defective apolipoprotein B variant is the cause of familial defective apo B-100 (FDB), an autosomal dominantly inherited disease, which leads to increased plasma cholesterol levels and premature atherosclerosis. Neither patient expressed FDB. It is concluded that the gene defect responsible for FDB is not involved in the pathogenesis of type III HLP.

For the low density lipoprotein receptor (LDLR), many mutations have been characterized which identify this gene as one with an important role in lipid metabolism in patients with familial hypercholesterolemia (FH). Genetic heterogeneity at this locus raises the possibility that the LDLR may also contribute to variation in cholesterol levels in the normocholesterolemic population. We have determined genotypes at the LDLR locus using restriction fragment length polymorphisms (RFLPs) detected with the enzymes StuI, ApalI, PvuII and NcoI in 324 normocholesterolemic individuals from Germany. A significant association (p less than 0.01) was detected between the cutting site for the PvuII RFLP and lower cholesterol levels, and variation associated with this polymorphism explains 3% of the sample variance in cholesterol levels. In family studies we have determined four-RFLP haplotypes of 148 independent LDLR genes and have observed 9 haplotypes in the population. Three of these haplotypes containing the cutting site for PvuII are associated with a reduction in plasma LDL-cholesterol levels. Phylogenetic analysis indicates that these three haplotypes are related by evolutionary history, and this suggests that a single functionally important sequence change in the LDLR explains our observations. Our data confirm other reports and strongly suggest that the LDLR locus may be one of those genes involved in determining serum cholesterol levels in the normal population.

The periodontal pathogen Tannerella forsythia expresses several glycosidases which are linked to specific growth requirements and are involved in the invasion of host tissues. α-l-Fucosyl residues are exposed on various host glycoconjugates and, thus, the α-l-fucosidases predicted in the T. forsythia ATCC 43037 genome could potentially serve roles in host-pathogen interactions. We describe the molecular cloning and characterization of the putative fucosidase TfFuc1 (encoded by the bfo_2737 = Tffuc1 gene), previously reported to be present in an outer membrane preparation. In terms of sequence, this 51-kDa protein is a member of the glycosyl hydrolase family GH29. Using an artificial substrate, p-nitrophenyl-α-fucose (KM 670 μM), the enzyme was determined to have a pH optimum of 9.0 and to be competitively inhibited by fucose and deoxyfuconojirimycin. TfFuc1 was shown here to be a unique α(1,2)-fucosidase that also possesses α(1,6) specificity on small unbranched substrates. It is active on mucin after sialidase-catalyzed removal of terminal sialic acid residues and also removes fucose from blood group H. Following knock-out of the Tffuc1 gene and analyzing biofilm formation and cell invasion/adhesion of the mutant in comparison to the wild-type, it is most likely that the enzyme does not act extracellularly. Biochemically interesting as the first fucosidase in T. forsythia to be characterized, the biological role of TfFuc1 may well be in the metabolism of short oligosaccharides in the periplasm, thereby indirectly contributing to the virulence of this organism. TfFuc1 is the first glycosyl hydrolase in the GH29 family reported to be a specific α(1,2)-fucosidase.

Many patients at high risk for coronary heart disease (CHD) are not readily identified by routine risk assessment in clinical practice and are consequently at risk for inadequate management. Peripheral arterial disease is a CHD risk equivalent, requiring intensive low-density lipoprotein cholesterol (LDL-C) lowering to the lowest recommended target levels; however, asymptomatic disease, although still associated with elevated risk, is not likely to be recognized in routine clinical practice. Heterozygous familial hypercholesterolaemia (FH) is associated with early and aggressive atherosclerotic disease, yet individuals with FH may go unrecognized in the absence of family screening. The metabolic syndrome is very common and is also associated with increased CHD risk, but affected individuals may not be identified if attention is not given to the relatively simple clinical criteria currently recommended for use in diagnosis. Although it is widely known that type 2 diabetes is associated with elevated CHD risk, the fact that statin treatment in diabetic patients is warranted even in those with relatively low LDL-C levels may not be widely appreciated. Recent modifications of the National Cholesterol Education Program Adult Treatment Panel III guidelines include optional reductions in both LDL-C goals and thresholds for initiating therapy in light of persuasive clinical trial evidence that patients at high risk and moderately high risk derive protective benefits from statin therapy even when treatment is started at LDL-C levels below prior goal or threshold levels. Increased vigilance for high-risk conditions that may elude routine risk assessment is necessary to ensure that all high-risk patients receive adequate treatment.

Despite the benefits of statin therapy, cholesterol management remains suboptimal and many patients do not achieve their recommended low-density lipoprotein cholesterol (LDL-C) goals. The use of insufficient doses, limited drug effectiveness and poor patient compliance may contribute to the treatment gap. Options for improving lipid management include dose titration, combination therapy or prescribing a more efficacious statin. LDL-C reductions are generally modest when patients' current statin dose is titrated, and there may be an increased potential for adverse effects. Combining statin therapy with another lipid-modifying agent can provide additional LDL-C reductions, but cost, tolerability and compliance should be considered. In general, switching to a more efficacious statin is a cost-effective way of enabling more patients to achieve recommended targets without increasing dosages. When considering the options available, physicians should balance efficacy, cost and safety to enable more patients to attain LDL-C goals and achieve greater therapeutic gain from statin treatment.

Electrically conductive heterogeneous binary polymer blends based on ethylene–propylene–diene-monomer (EPDM) and polyaniline (PAni) were prepared in a Haake Rheocord 90 rheometer, coupled with an internal mixer (counter rotating cam rotors) using different amounts of PAni doped with dodecylbenzenosulfonic acid (DBSA). Blends were crosslinked using two methods: (i) phenolic resin (SP-1045) as crosslinking agent and (ii) electron beam irradiation. The last method avoids the interference of the acid dopant in the crosslinking process and produces blends with higher conductivity.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Purpose An increasing number of reports suggest that Propionibacterium acnes can cause serious invasive infections. Currently only limited data exist regarding the spectrum of invasive P. acnes infections. Methods Non-selective cohort study at a tertiary hospital in the UK over a nine-year-period (2003-2012) investigating clinical manifestations, risk factors, management and outcome of invasive P. acnes infections. Results Forty-nine cases were identified; the majority were neurosurgical infections and orthopaedic infections (n=28 and n=15, respectively). Only two cases had no predisposing factors; all neurosurgical and 93.3% of orthopaedic cases had a history of previous surgery and/or trauma. Foreign material was in situ at the infection site in 59.3% and 80.0% of neurosurgical and orthopaedic cases, respectively. All neurosurgical and orthopaedic cases required one or more surgical interventions to treat P. acnes infection, with or without concomitant antibiotic therapy; the duration of antibiotic therapy was significantly longer in the group of orthopaedic cases (median 53 versus 19 days; p=0.0025). All tested P. acnes isolates were susceptible to penicillin, ampicillin and chloramphenicol; only one was clindamycin-resistant. Conclusions Neurosurgical and orthopaedic infections account for the majority of invasive P. acnes infections. The majority of cases have predisposing factors, including previous surgery and/or trauma; spontaneous infections are rare. Foreign material is commonly present at the site of infection, indicating that the pathogenesis of invasive P. acnes infections likely involves biofilm formation. Since invasive P. acnes infections are associated with considerable morbidity, further studies are needed to establish effective prevention and optimal treatment strategies.

We have identified the cytosine to thymine change in the codon for amino acid 408 which causes valine to be replaced by methionine in exon 9 of the LDL receptor gene in a 12-year-old Greek boy living in Germany, with homozygous familial hypercholesterolemia, by using polymerase chain reaction-amplified genomic DNA and subsequent restriction digestion. Homozygosity was confirmed by direct DNA sequencing. The mutation was present in both his parents, and his brother, grandmother, uncle and cousin. Six restriction fragment length polymorphisms of the LDL receptor gene were used to determine the haplotype of the defective allele. The haplotype was different from the one reported earlier in African Afrikaners and from Holland. We conclude that the mutation in the Greek boy probably occurred as an independent mutation. Because the parents are from different areas in Greece, this mutation may be common in Greeks.

Supersilyl alk. metals (alkali supersilanides) tBu3SiM without or with donors (Do) like ethers, amines, arom. hydrocarbons are easily obtained by the action of alk. metals M on supersilyl halides tBu3SiX above room temp. in alkanes or donor-solvents like THF, benzene: tBu3SiX + 2M -> tBu3SiM + MX; tBu3SiM + nDo -> tBu3SiM(Do). Ethers as donors can be exchanged by stronger donors like PMDTA, 18-crown-6, cryptand-222. In particular the following extremely water and air sensitive compds. are prepd.: yellow tBu3SiLi (as to x-ray structure anal. dimeric with Si...Li...Si contacts), orange yellow tBu3SiNa (as to x-ray structure anal. dimeric with Si...Na...Si contacts), light-yellow tBu3SiK (as to its insoly. in alkanes polymeric), tBu3SiM (M = Rb, Cs; insol. in alkanes), light-yellow to colorless tBu3SiLi(THF)2 (probably monomeric), light-yellow tBu3SiNa(THF)2 (as to x-ray structure anal. dimeric with CH3...Na contacts), light-yellow tBu3SiNa(OBu2)2 (probably analogously structured as the THF adduct), yellow tBu3SiK(THF)n (loses THF; stable only in THF), light-yellow tBu3SiNa(PMDTA) (as to x-ray structure anal. monomeric), orange-red tBu3SiK(Benzene)3 (as to x-ray structure anal. monomeric), orange-yellow tBu3SiNa(18-C-6) (unstable as to its tendency to deprotonate 18-crown-6), tBu3SiM(C222) (M = Na, K; not isolable as to its tendency to deprotonate cryptand-222). Because of the high tendency of the anionic part tBu3Si- of the compds. mentioned for delivering electrons, the supersilyl alk. metals act as strong bases which deprotonate even weak bases such as THF or benzene under formation of supersilane tBu3SiH. Over and above that, they work as good nucleophiles and reducing agents which for example react with Me3SiX under formation of trimethylsilylsupersilane Me3Si-SitBu3 and with Ag+NO3- under formation of superdisilane tBu3Si-SitBu3. As the supersilyl alk. metals may even be oxidized by supersilyl halides in alkanes at 100 Deg by way of tBu3SiM + tBu3SiX -> tBu3Si. + MX + tBu3Si., and tBu3Si. + RH -> tBu3SiH + R., and 2tBu3Si..dblarw.(tBu3Si)2, the formation of tBu3SiM from tBu3SiI and K, Rb, Cs at elevated temps. in satd. hydrocarbons is accompanied by the formation of supersilane, superdisilane and secondary products of R.. [on SciFinder (R)]

Amongst prospective starting materials for organic synthesis, terminal (monosubstituted) alkenes are ideal. In the form of α-olefins, they are manufactured on enormous scale and they are the core product features from many organic chemical reactions. While their latent reactivity can easily enable hydrocarbon chain extension, alkenes also have the attractive feature of being stable in the presence of many acids, bases, oxidants and reductants. In spite of these impressive attributes, relatively few catalytic enantioselective transformations have been developed that transform aliphatic α-olefins in >90% ee and, with the exception of site-controlled isotactic polymerization of α-olefins,1 none of these processes result in chain-extending C-C bond formation to the terminal carbon.2, 3, 4, 5, 6 Herein, we describe a strategy that directly addresses this gap in synthetic methodology and present a single-flask catalytic enantioselective conversion of terminal alkenes into a range of chiral products. These reactions are enabled by an unusual neighboring group participation effect that accelerates Pd-catalyzed cross-coupling of 1,2-bis(boronates) relative to nonfunctionalized alkyl boronate analogs. In tandem with enantioselective diboration, this reactivity feature connects abundant alkene starting materials to a diverse array of chiral products. Importantly with respect to synthesis utility, the tandem diboration/cross-coupling reaction (DCC reaction) generally provides products in high yield and high selectivity (>95:5 enantiomer ratio), employs low loadings (1–2 mol %) of commercially available catalysts and reagents, it offers an expansive substrate scope, and can address a broad range of alcohol and amine synthesis targets, many of which cannot be easily addressed with current technology.

The current paper outlines the concept of the constitutive equations of the ‘one-parameter model’ describing the inelastic mechanical behavior of metals. It concentrates on the version developed for a high temperature alloy, INCOLOY alloy 800H

The damage mechanisms influencing the axial strain-controlled Low-Cycle Fatigue (LCF) behavior of alloy 800H at 850 C have been evaluated under conditions of equal tension/compression ramp rates (Fast-Fast (F-F): 4 X 10(sup -3)/s and Slow-Slow (S-S): 4 X 10(sup -5)/s) and asymmetrical ramp rates (Fast-Slow (F-S): 4 x 10(sup -3)/s / 4 X 10(sup -5/s and Slow-Fast (S-F): 4 X 10(sup -5) / 4 X 10(sup -3)/s) in tension and compression. The fatigue life, cyclic stress response, and fracture modes were significantly influenced by the waveform shape. The fatigue lives displayed by different loading conditions were in the following order: F-F greater than S-S greater than F-S greater than S-F. The fracture mode was dictated by the ramp rate adopted in the tensile direction. The fast ramp rate in the tensile direction led to the occurrence of transgranular crack initiation and propagation, whereas the slow ramp rate caused intergranular initiation and propagation. The time-dependent processes and their synergistic interactions, which were at the basis of observed changes in cyclic stress response and fatigue life, were identified. Oxidation, creep damage, dynamic strain aging, massive carbide precipitation, time-dependent creep deformation, and deformation ratcheting were among the several factors influencing cyclic life. Irrespective of the loading condition, the largest effect on life was exerted by oxidation processes. Deformation ratcheting had its greatest influence on life under asymmetrical loading conditions. Creep damage accumulated the greatest amount during the slow tensile ramp under S-F conditions.

The effects of strain rate (4 x 10(exp -6) to 4 x 10(exp -3)/s) and temperature on the Low-Cycle Fatigue (LCF) behavior of alloy 800H have been evaluated in the range 750 C to 950 C. Total axial strain controlled LCF tests were conducted in air at a strain amplitude of +/- 0.30 pct. LCF life decreased with decreasing strain rate and increasing temperature. The cyclic stress response behavior showed a marked variation with temperature and strain rate. The time- and temperature- dependent processes which influence the cyclic stress response and life have been identified and their relative importance assessed. Dynamic strain aging, time-dependent deformation, precipitation of parallel platelets of M(23)C6 on grain boundaries and incoherent ledges of twins, and oxidation were found to operate depending on the test conditions. The largest effect on life was shown by oxidation processes.

This research links two important higher education phenomena: potential “brain drain” among academics abroad and the U.S. academic labor market. The inquiry draws on the “brain drain” literature and is grounded primarily on a secondary analysis of a major survey (1989) of British university and polytechnic faculty members. The anlaysis shows that fully 40.0 percent of university faculty are “seriously considering” a move abroad with the substantial majority favoring the United States as a destination. Faculty characteristics—including academic field, research versus teaching orientation, rank, age, gender, and political identification—are correlated with faculty members' professed interest in emigration. The analysis also compares (former) polytechnic to university faculty as well as to a subset of Oxford and Cambridge faculty.

Frostegård et al. (J Lipid Res 1990;31:37-44) demonstrated that the proliferation of the human monocyte cell line U937 is critically dependent on the uptake of low-density lipoprotein (LDL) via the apo B, E (LDL) receptor, a characteristic that was used to detect patients with familial defective apolipoprotein B-100 (FDB). Here we applied this principle to develop a simple and reproducible assay for the detection of patients with functionally defective LDL. We added serum to U937 cells in cholesterol-free incubation medium and determined the increase in cell number after a 72-h incubation at 37 degrees C by using an electronic cell counter. Sera from 10 normolipidemic individuals and from 34 patients with type IIa hyperlipoproteinemia stimulated the growth of U937 cells in proportion to the exogenous cholesterol concentration (r = 0.83, P < 0.001) and the LDL-cholesterol concentration (r = 0.81, P < 0.001). However, sera from 16 patients with FDB stimulated less cell proliferation than did sera from patients with type IIa hyperlipoproteinemia with equal LDL-cholesterol concentrations. With a 15% reduction in growth as the cutoff value, this test had a sensitivity and specificity for diagnosis of FDB of 87.5% and 100%, respectively. The improved U937 monocyte proliferation assay can be used for screening hypercholesterolemic patients to detect individuals with functionally defective LDL.

Chiral monodentate ligands are important tools for the control of enantioselectivity in catalytic reactions. These compounds are particularly important when transition metal catalysts lack sufficient coordination sites to bind a bidentate ligand and still retain activity. Along these lines, modular, tunable chiral carbenes[1] and phosphoramidites[2] have found particular prominence in the field of asymmetric catalysis. Aside from these compound classes, however, there is a relative paucity of effective, tunable monodentate chiral ligands that have found widespread utility. In recent studies on platinum-catalyzed enantioselective diene diboration, we achieved limited success when optimizing chiral phosphoramidite and phosphonite ligands for certain substrates.[3,4] Because catalytic diboration benefits from the presence of electron-rich monodentate phosphines[5], we considered that solutions to problematic substrates might arise from the availability of a readily preparable, tunable, chiral, Lewis basic phosphine ligand.[6] In this manuscript, we describe the synthesis and properties of enantiomerically enriched modular 1,3-oxaphospholanes (termed OxaPhos ligands, Scheme 1). These ligands are readily available from the combination of an enantiopure epoxide, a primary phosphine, and a ketone or the derived ketal.[7] In addition to describing their synthesis and properties, we also describe their use in the catalytic 1,4-diboration of challenging diene substrates.

In order to investigate the effect on creep strength of the selective oxidation of chromium which causes the formation of a carbide-fi-ee subsurface zone, specimens of Ni22Cr12Co9Mo1Al (Alloy 617) were subjected to heat treatments to simulate a long-term service exposure of a thin-walled heat exchanger tube operating at high temperatures. In creep tests carried out at 900°C, specimens with extensive chromium-depleted and carbide-free subsurface zones exhibited higher creep strength than specimens thermally aged for the same durations, but having no carbide-free zone. The carbon released by dissolution of the carbides in the chromium-depleted zone migrated to the centre of the specimen, producing enhanced carbide precipitation. This led to an increase in the creep strength of the specimen core which offset the loss in creep strength of the subsurface zone.

Oxidation studies have been carried out on NiCrAl-base alloys in air and air containing 1% sulphur dioxide at 1000-degrees-C. The alloys used were in the cast, forged and single-crystalline form. There was considerable difference in the oxidation behavior of the as-cast alloy and that of forged alloy, when the environment contained sulphur dioxide. In the absence of the latter, the behavior of the two alloys was not very different. The oxidation behavior of the single crystals was also very similar to that of the cast and forged alloys, when the atmosphere was oxidizing. A few single-crystalline alloys, however, underwent catastrophic oxidation when about 1% sulphur dioxide gas was present, in a manner similar to that of the cast alloy. Oxidation tests at 1000-degrees-C as well as detailed scale analysis indicated that the different microstructure, especially large difference in grain size was probably the main reason for the large difference in their oxidation behavior.

Familial defective apolipoprotein B-100 (FDB) is characterized by a decreased affinity of low density lipoprotein (LDL) to the LDL receptor resulting in a dominantly inherited increase of plasma LDL. It is postulated that FDB is caused by a G to A mutation at nucleotide 10,708 in exon 26 of the apoB gene creating a substitution of glutamine for arginine in amino acid 3500. The arginine(3500)-->glutamine mutation has been identified on the same haplotype of the apoB gene in several populations from North America and Europe, suggesting that it occurred on a single ancestral gene. Independent mutations were not observed. The purpose of this paper is to report on a family where individuals show a dominantly inherited increase of plasma LDL associated with an independent arginine(3500)-->glutamine mutation as determined by haplotype analysis using polymorphic markers of the apoB gene. The identification of these individuals is strong evidence that the arginine(3500)-->glutamine mutation is causative for the defective binding of apoB-100.

The oxidation behaviour of TiAl-base intermetallics has been investigated at 800°C in air. The main emphasis was placed on the mechanism by which niobium additions decrease the oxidation rate of titanium aluminides. For this purpose specimens of Ti50Al and Ti45Al10Nb were oxidized in a two-stage oxidation technique using an 18O-tracer. The scale formed during this oxidation process was analyzed by SNMS. It was found that niobium is mainly incorporated in the titanium dioxide and the nitride scale which forms beneath the initially formed alumina layer. The effect of this behaviour of the niobium on the oxide scale growth rates is discussed.

In high temperature alloys, the selective oxidation of chromium to form a chromia scale leads to subsurface depletion of chromium in the alloy which in turn leads to the dissolution of chromium carbide in the depleted zone. The effect of this carbide depleted subsurface zone on the creep properties of Inconel Alloy 617 (Ni–22Cr–12Co–9Mo–1Al–0·08C; wt-%) has been determined. The specimens were subjected to heat treatments before creep testing to simulate long term service exposure of a thin walled heat exchanger tube operating at high temperatures. It was found, surprisingly, that in creep tests carried out at 900°C, specimens having extensive chromium depleted and carbide free subsurface zones exhibit higher creep strength than specimens thermally aged for the same durations, but having no chromium depleted zone. As chromium was removed from the matrix owing to selective oxidation, the carbon, released as the carbides in the chromium depleted zone dissolved, migrated to the centre of the specimen...

Fiber scaffolds of bioactive polysialic acid have been prepared via electrospinning for peripheral nerve regeneration. The diameter, morphology and alignment of fibers in scaffolds were adjusted by variation of electrospinning parameters, which are decisive for the cell-scaffold interaction. Due to the high water solubility of polysialic acid (poly-alpha-2,8-N-acetylneuraminic acid) a photoactive derivative (poly-alpha-2,8-N-pentenoylneuraminic acid) was used to obtain stable fiber scaffolds in water by photochemical crosslinking. At the optimized fiber scaffolds good cell viability and directed cell proliferation along the fibers was achieved by cell tests with immortalized Schwann cells.

In the majority of patients, familial hypercholesterolaemia (FH) is caused by different mutations affecting the well defined low density lipoprotein receptor (LDLR) gene. However, 3% of patients in Munich with a clinical diagnosis of FH have a particular mutation in the apolipoprotein B gene causing familial defective apolipoprotein B-100 (FDB). To date none of the LDLR mutations causing FH in German patients has been identified and it is therefore not yet possible to use DNA technology for direct diagnosis. However, indirect molecular diagnosis based on genetic linkage of common restriction fragment length polymorphisms (RFLPs) of the LDLR gene can be used for diagnosis in family studies. Patients with FDB were excluded from this study. Genotypes and haplotypes of four RFLPs (StuI, ApalI 5', PvuII, and NcoI) were determined in a total of 164 independent alleles from 31 pedigrees that included 222 subjects. Allele frequencies and four RFLP haplotype distribution did not differ significantly from those reported in other populations. The applicability of DNA diagnosis in our lipid clinic is comparable with the estimation from calculations on frequencies and heterozygosities of RFLPs, as predicted using these four RFLPs before. On the basis of cosegregation of haplotypes and normo- or hypercholesterolaemia in one or more sibs or offspring, defective and normal LDLR gene alleles could be distinguished in 42 of 58 heterozygous FH patients who were heterozygous for at least one RFLP. In 97 of 134 (72%) children of these 42 subjects, diagnosis of FH could be carried out unambiguously.(ABSTRACT TRUNCATED AT 250 WORDS)

A 15 year old girl experienced Horner's syndrome on the right side, paraesthesia of the right arm and meningitis. CT and MRI showed a cystic lesion on the right side of the cervical spine at C3/C4 which descended with an extraspinal portion down to C6. Histology revealed a complex neurenteric cyst. The ipsilateral vertebral artery showed an atypical course. This abnormal artery besides a partial fusion of the vertebrae C2/C3/C4 suggest a complex malformation at the site of the cyst. Disturbed developmental relationships in this case indicate that pathological blood vessels may represent a risk factor in the surgical treatment of neurenteric cysts.

To study the allelic variation at the human LDL-receptor gene locus in a number of individuals with familial hypercholesterolemia, a protocol was applied for direct sequence analysis of genomic DNA. The asymmetric polymerase chain reaction (PCR) was used to synthesize single-stranded DNA. Sequencing was carried out with modified T7 DNA polymerase (Sequenase version 2.0, United States Biochemical) after purification of the amplification product with a glass powder adhesion method. The method is sensitive enough to identify the heterozygous state of allelic variation and bypasses cumbersome cloning and subcloning procedures. Here we report the occurrence of a guaninine-to-adenine change in the codon for amino acid 655. However, the glycine residue is not replaced by the base change at this position, and the mutation observed here does not represent the underlying genetic defect of the LDL-receptor defect in this individual. Preliminary data suggest that this mutation represents a rare genetic variation.

"Enhancing Faculty Careers" examines the key factors that bear on professional growth, including the role of professional schools in the preparation of prospective faculty, career consulting, wellness programs, employee assistance programs to help deal with substance abuse, and strategies for instituting early retirement programs.

It has recently been suggested that a substitution of glutamine for arginine at residue 3500 of apolipoprotein (apo) B-100 causes familial defective apo B-100 (FDB), an autosomal, dominantly inherited disorder, which leads to increased serum cholesterol levels. From a sample of 243 patients from Munich with type IIa hyperlipoproteinemia (HL), we have identified eight individuals with the apo B-100 arginine(3500)----glutamine mutation. In a group of 57 subjects with defective low density lipoprotein receptor (LDLR), no mutant apo B alleles were detected. The frequency of FDB in patients with type IIa HL was estimated to be 3%. In the kindreds of three of the probands, 10 additional carriers of the apo B mutation were identified. Clinical and biochemical data reveal a striking similarity between patients with FDB and those with a defect in the LDLR gene. Our data support previous findings that FDB is a serious disorder causing premature atherosclerosis.